Abstract
Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation.
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Acknowledgements
We thank all family members who participated in this study, E. Milz, A. Alver and A. Coffey for excellent technical assistance, F. Kokocinski and A. Palotie for experimental design, and C. Kubisch, B. Wirth and K. Boss for critical reading the manuscript. The CINP antibody was a kind gift from D. Cortez (Nashville, Tennessee, USA). This work was supported by the German Federal Ministry of Education and Research (BMBF) by grant numbers 01GM0880 (SKELNET) and 01GM0801 (E-RARE network CRANIRARE) to B.W., the Karadeniz Technical University Research Fund by grant numbers 2008.114.001.02 and 2008.114.001.12 to E.K., the Medical Research Council and Lister Institute to A.P.J. and by the Wellcome Trust, grant 077014/Z/05/Z.
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The project was conceived and the experiments were planned by E.K. and B.W. We would like to note that Y.A. and K.E.B. had a comparable contribution to this study. The review of phenotypes and the sample collection were performed by B.W., E.K., Y.A., A.P.J., H.K., B. Tüysüz, W.K., B. Toraman., S. Kayipmaz, S. Kul, M.I., K.M., H.D., D.W., H.G.B. and A.R. Experiments were performed by E.K., G.Y., K.E.B., E.P., L.S.B., Y.L., M.K., I.B., K.B., D.J.T. and C.S. Data analysis was performed by B.W., E.K., G.N., P.N., A.K., J.A., M.S.T., M.H. and A.P.J. The manuscript was written by B.W., G.Y., E.K. and K.E.B. All aspects of the study were supervised by B.W.
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Supplementary Figures 1–8, Supplementary Tables 1–4 and Supplementary Methods (PDF 4081 kb)
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Kalay, E., Yigit, G., Aslan, Y. et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet 43, 23–26 (2011). https://doi.org/10.1038/ng.725
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DOI: https://doi.org/10.1038/ng.725
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